Tumor–stroma interactions are of key importance for pancreatic ductal adenocarcinoma (PDAC) progression. Our aim was to investigate whether cancer associated fibroblasts (CAFs) and mast cells (MC) affected the sensitivity of PDAC cells to gemcitabine/nabpaclitaxel (GEM/NAB). For this purpose, the combination cytotoxicity and the effect on tumor invasion and angiogenesis were evaluated with or without a conditioned medium from the mast cell line HMC-1 (human mast cell line-1 cells) and CAFs. Beside the clinical outcome of a homogenous population of PDAC patients, receiving GEM/NAB, was correlated to the circulating levels of mast cell tryptase and to a panel of inflammatory and immunosuppressive cytokines. CAFs neither affected drugs’ cytotoxicity nor the inhibition of angiogenesis, but promoted tumor cell invasion. The MC instead, caused resistance to drugs by reducing apoptosis, by activating the TGF-β signalling and by promoting tumor invasion. Indeed, the inhibition of TβRI serine/threonine kinase activity by galunisertib restored drugs cytotoxicity. Moreover, MC induced the release of TGF-β1, and increased expression of PAR-2, ERK1/2 and Akt activation. Accordingly, TGF-β1, tryptase and other pro-inflammatory and immunosuppressive cytokines increased in the unresponsive patients. In conclusion, MC play a pivotal role in the resistance to GEM/NAB. A correlation between high level of circulating pro-inflammatory/ immunosuppressive cytokines and unresponsiveness was found in PDAC patients.

Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed similar results in terms of survival in a non-inferiority randomized trial study considering the same subset of patients. Unlike other targeted therapies, predictive and prognostic markers in HCC patients treated with sorafenib are lacking. Their identification could help clinicians in the daily management of these patients, mostly in light of the new therapeutic options available in the first.

Skeletal metastases of unknown primary (SMUP) represent a clinical challenge in dealing with patients diagnosed with bone metastases. Management of these patients has improved significantly in the past few years. however, it is fraught with a lack of evidence. While some patients have achieved impressive gains, a more systematic and tailored treatment is required. Nevertheless, in real-life practice, the outlook at the beginning of treatment for SMUP is decidedly somber. An incomplete translational relevance of pathological and clinical data on the mortality and morbidity rate has had unsatisfactory consequences for SMUP patients and their physicians. We examined several approaches to confront the available evidence; three key points emerged. The characterization of the SMUP biological profile is essential to driving clinical decisions by integrating genetic and molecular profiles into a multi-step diagnostic work-up. Nonetheless, a pragmatic investigation plan and therapy of SMUP cannot follow a single template; it must be adapted to different pathophysiological dynamics and coordinated with efforts of a systematic algorithm and high-quality data derived from statistically powered clinical trials. The discussion in this review points out that greater efforts are required to face the unmet needs present in SMUP patients in oncology.

Pancreatic cancer represents a modern oncological urgency. Its management is aimed to both distal and local disease control. Resectability is the cornerstone of treatment aim. It influences the clinical presentation’s definitions as up-front resectable, borderline resectable and locally advanced (unresectable). The main treatment categories are neoadjuvant (preoperative), definitive and adjuvant (postoperative). This review will focus on (i) the current indications by the available national and international guidelines; (ii) the current standard indications for target volume delineation in radiotherapy (RT); (iii) the emerging modern technologies (including particle therapy and Magnetic Resonance [MR]-guided-RT); (iv) stereotactic body radiotherapy (SBRT), as the most promising technical delivery application of RT in this framework; (v) a particularly promising dose delivery technique called simultaneous integrated boost (SIB); and (vi) a multimodal integration opportunity: the combination of RT with immunotherapy.

After a timing preoperative staging, treatment of resectable pancreatic adenocarcinoma (PDAC) includes surgery and adjuvant therapies, the former representing the initial therapeutic option and the latter aiming to reduce the incidence of both distant metastases (chemotherapy) and locoregional failures (chemoradiotherapy). Herein, we provide a critical overview on the role of multimodal treatment in PDAC and on new opportunities related to current more active poli-chemotherapy regimens, targeted therapies, and the more recent immunotherapy approaches. Moreover, an analysis of pathological markers and clinical features able to help clinicians in the selection of the best therapeutic strategy will be discussed. Lastly, the role of neoadjuvant treatment of initially resectable disease will be considered mostly in patients whose malignancy shows morphological but not clinical or biological criteria of resectability. Depending on the results of these investigational studies, today a multidisciplinary approach can offer the best address therapy for these patients.